Increased bone resorption is central to the pathogenesis of osteoporosis. Several disorders of parathyroid function that occur with aging cause increased resorption and contribute to the bone loss seen in this disease. These include, an age-related rise in circulating levels of PTH, an increased prevalence of primary and secondary hyperparathyroidism and increased skeletal sensitivity to the resorbing actions of PTH following menopause. We have generated evidence that the interleukin6/interleukin-6 soluble receptor cytokine system (IL-6/IL-6sR) plays a critical role in PTH-mediated bone resorption. Circulating levels of IL-6 and IL-6sR are elevated in states of parathyroid hormone excess and correlate strongly with markers of bone resorption and rates of bone loss. PTH infusion in vivo causes serum levels of IL-6 and IL-6sR to rise and neutralizing IL-6 in vivo blocks PTH-induced bone resorption. Surprisingly, the liver contributes substantially to the PTH-induced increases in circulating IL-6/IL-6sR, with organ production rates sufficient to entirely explain the changes in circulating cytokine levels. To further explore these findings, we will: (1) define the role of hepatic IL-6 in PTH-induced bone resorption by generating mice with conditional knockout of IL-6 in hepatocytes and conditional knockout of the PTH receptor in hepatocytes. This will allow us to selectively eliminate the contribution of the liver to the changes induced by PTH in circulating IL-6/IL-6sR; (2) determine whether IL-6/IL-6sR acts co-operatively with RANKL, in either an additive or synergistic fashion to mediate PTH-induced bone resorption. The effects of IL-6/IL-6sR and RANKL separately and together on osteoclastogenesis and osteoclast activity will be determined in vitro. The effects of separate or combined infusions of IL-6/IL-6sR and RANKL in mice, at doses that match serum levels induced by PTH, will be used to determine in vivo additivity and to assess the contribution of circulating cytokines to the resorbing actions of PTH; (3) the role of the liver in PTH-induced increases in RANKL will be determined as well as the role of IL-6/IL-6sR in inducing soluble RANKL release in bone and liver. Finally, PTH infusions in women will allow us to determine whether the changes in serum RANKL levels seen in mice also occur in humans. These studies will better define the role of IL-6 in PTH-induced bone resorption, clarify its mechanisms of action and have important therapeutic implications.